Tumor Necrosis Factor (TNF) is a multifunctional cytokine involved in the protection of the organism, but when overproduced it can play a major pathogenic role in several diseases. TNF is known to be involved in inflammatory processes and to be a mediator of the damage to tissues in rheumatic diseases (Beutler, B. and Cerami, C. NEJM 316:379-385 (1987)) and of the damage observed in graft-versus-host reactions (Piguet, P. F. et al. J. Exp. Med. 166:1280-89 (1987)).
Two TNF Binding Proteins, designated TBP-I and TBP-II were described in U.S. patent application Ser. No. 07/243,092 filed Sep. 12, 1990 and 07/524,263, filed May 16, 1990, respectively, from the laboratory of the present inventors, and shown to protect cells from TNF toxicity and to interfere with the binding of TNF to cells. Later studies have shown that these two proteins are structurally related to two molecular species of the cell surface TNF receptors (TNF-R) and that, indeed, TBP-I is related to a soluble form of the TNF type I receptor, while TBP-II is related to a soluble form of the TNF type II receptor (Engelmann, H. et al. J. Biol. Chem. 264:11974-11980 (1989); Engelmann, H. et al. J. Biol. Chem. 265:1531-1536 (1990)). Like the cell surface receptors for TNF, the soluble forms of these receptors specifically bind TNF and can thus interfere with its binding to cells, functioning as physiological inhibitors of TNF activity. Although the primary function of the immune system is to protect an individual against infection by foreign invaders such as microorganisms, it may happen that the immune system attacks the individual's own tissues, leading to pathologic states known as autoimmune diseases, which are frequently associated with inflammatory processes. Examples of autoimmune diseases are rheumatoid arthritis, juvenile onset type I diabetes mellitus, systemic lupus erythematosus, thyroiditis and multiple sclerosis. Rheumatoid arthritis is a disease marked by signs and symptoms of inflammation of the joints. Systemic lupus erythematosus (SLE) is characterized by red, scaley patches on the skin, and by malfunction of the kidneys at the advanced stage of the disease, and is associated with inflammatory reactions triggered by deposition of immune complexes in blood vessels, particularly in the kidneys. Multiple sclerosis is a human illness characterized by relapsing, inflammatory conditions that can cause weakness, body tremors and, in extreme cases, paralysis, and is associated with immune system attack of the protective myelin sheath surrounding peripheral nerve cells.
TNF has been associated with inflammatory processes in systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. In published European patent applications of the same assignee No. 398327 and 412486, it is disclosed that in SLE patients the serum levels of both TBP-I and TBP-II are significantly elevated and in correlation with the disease activity, indicating that TBP-I and TBP-II may be used as sensitive markers of the disease activity and may be useful in monitoring immune activation related to disease activity in SLE patients as well as in patients with other autoimmune diseases.